The Mosquito Effect: Regulatory and effector T cells acquire cytoplasmic material from tumor cells through intercellular transfer
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ABSTRACT:
PROVIDER: PRJNA1033344 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26557500_1.fastq.gz | Fastqsanger.gz | |||
| SRR26557500_2.fastq.gz | Fastqsanger.gz | |||
| SRR26557501_1.fastq.gz | Fastqsanger.gz | |||
| SRR26557501_2.fastq.gz | Fastqsanger.gz | |||
| SRR26557502_1.fastq.gz | Fastqsanger.gz |
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Project description:The phenomenon of intercellular transfer of cellular material, including membranes, cytoplasm, and even organelles, has been observed for decades. The functional impact and molecular mechanisms of such transfer in the immune system remain largely elusive due to the absence of a robust in vivo model. Here, we introduce a new tumor mouse model, where tumor cells express the soluble ultra-bright fluorescent protein ZsGreen, which allows detection and measurement of intercellular transfer of cytoplasm from tumor cells to infiltrating immune cells. We found that in addition to various types of myeloid lineage cells, a large fraction of T regulatory cells and effector CD8 T cells acquire tumor material. Based on the distribution of tumor-derived ZsGreen, the majority of T cells integrate captured cytoplasm into their own, while most myeloid cells store tumor material in granules. Furthermore, scRNA-seq analysis revealed significant alterations in transcriptomes of T cells that acquired tumor cell cytoplasm, suggesting potential impact on T cell function. We identified that the participation of T cells in intercellular transfer requires cell-cell contact and is strictly dependent on the activation status of T lymphocytes. Finally, we propose to name the described phenomenon of intercellular transfer for tumor infiltrating T cells the “mosquito effect”.
2023-12-15 | GSE246498 | GEO
Project description:The phenomenon of intercellular transfer of cellular material, including membranes, cytoplasm, and even organelles, has been observed for decades. The functional impact and molecular mechanisms of such transfer in the immune system remain largely elusive due to the absence of a robust in vivo model. Here, we introduce a new tumor mouse model, where tumor cells express the soluble ultra-bright fluorescent protein ZsGreen, which allows detection and measurement of intercellular transfer of cytoplasm from tumor cells to infiltrating immune cells. We found that in addition to various types of myeloid lineage cells, a large fraction of T regulatory cells and effector CD8 T cells acquire tumor material. Based on the distribution of tumor-derived ZsGreen, the majority of T cells integrate captured cytoplasm into their own, while most myeloid cells store tumor material in granules. Furthermore, scRNA-seq analysis revealed significant alterations in transcriptomes of T cells that acquired tumor cell cytoplasm, suggesting potential impact on T cell function. We identified that the participation of T cells in intercellular transfer requires cell-cell contact and is strictly dependent on the activation status of T lymphocytes. Finally, we propose to name the described phenomenon of intercellular transfer for tumor infiltrating T cells the "mosquito effect".
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Project description:Intercellular cytoplasmic material transfer (MT) occurs between transplanted and developing photoreceptors and ambiguates cell origin identification in developmental, transdifferentiation, and transplantation experiments. Whether MT is a photoreceptor-specific phenomenon is unclear. Retinal ganglion cell (RGC) replacement, through transdifferentiation or transplantation, holds potential for restoring vision in optic neuropathies. During careful assessment for MT following human stem cell-derived RGC transplantation into mice, we identified RGC xenografts occasionally giving rise to labeling of donor-derived cytoplasmic, nuclear, and mitochondrial proteins within recipient Müller glia. Critically, nuclear organization is distinct between human and murine retinal neurons, which enables unequivocal discrimination of donor from host cells. MT was dependent on internal limiting membrane disruption, which is also required for retinal engraftment following transplantation. Our findings demonstrate that retinal MT is not unique to photoreceptors and challenge the isolated use of species-specific immunofluorescent markers for xenotransplant identification. Assessment for MT is critical when analyzing neuronal replacement interventions.
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Project description:Rare intercellular material transfer as a confound to interpreting inner retinal neuronal transplantation
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Project description:Metastasis is a major cause of mortality, and remains a final frontier in the search for a cure for cancer. While there has been much research on the ‘seed’ (metastatic tumor cells) and the ‘soil’ (colonized host tissue), interactions between metastatic cancer cells and stromal endothelial cells, which occur at multiple stages during metastasis, are less well understood. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for intercellular communication in vitro and in vivo, including horizontal transfer of microRNAs (miRNA). The communication between the tumor cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of “metastatic hijack”: cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in syngeneic- and human xenograft-breast cancer models. Targeting the formation of these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer. A miRNA microarray was used to evaluate the transport of endogenous microRNAs. The intercellular transfer-ve and intercellular transfer+ve samples were sorted from the same endothelial cell population with the only difference being the occurrence of intercellular transport. The heat map shows potential miRNA candidates for exogenous transfer on two independent biological replicates. These miRNA candidates were significantly up-regulated in the cells receiving transfer of intercellular contents. HUVECs that were not exposed to cancer cells were used as a baseline control.
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Project description:Mitochondrial loss and dysfunction drive T cell exhaustion and represent major barriers to successful T cell immunotherapies. We found that mesenchymal stromal cells (MSC) establish nanotubular connections with T cells in a TLN2-dependent manner and leveraged these intercellular highways to supply new mitochondria to CD8+ T cells. Acquisition of MSC mitochondria increased T cell basal mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, tumor-specific CD8+ T cells with donated mitochondria expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared to CD8+ T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. To unravel the mechanisms behind mitochondrial transfer we performed RNA sequencing on CD8+ T cells that acquired donor mitochondria (MitoPositive), or did not acquire donor mitochondira (MitoNegative) directly after after co-culture (0hr timepoint).
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Project description:Germ cell connectivity via intercellular bridges is a widely conserved feature but its functional significance is poorly understood. Intercellular bridges are essential for fertility in male mice as genetic ablation of a critical bridge component, TEX14, causes loss of germ cell connectivity and meiotic failure, however the underlying reasons are unknown. A screen for meiosis-defective mouse mutants yielded a sterile mutant harboring a point mutation in Tex14 that leads to a partial loss of germ cell intercellular bridges. We utilized the Tex14 hypomorphs with reduced intercellular bridges, along with Tex14-null mice that completely lack bridges to examine the roles of germ cell connectivity during adult spermatogenesis. Complete or partial loss of intercellular bridges does not severely deplete spermatogonia, but spermatocytes are unable to undergo meiotic DNA replication and enter meiotic prophase. Phenotypic severity correlates with the extent of intercellular bridge depletion, with Tex14 hypomorphs containing a relatively larger number of spermatocytes undergoing meiosis, thus allowing us to assess impacts on meiotic progression. Tex14-deficient germ cells that enter prophase form meiotic breaks and initiate synapsis, but later exhibit synaptic failures and retain unrepaired breaks. Strikingly, Tex14-deficient germ cells derepress LINE1 retrotransposons and accumulate LINE1-encoded proteins during meiosis. Single-cell RNA-sequencing of testes from Tex14 hypomorphs show that intercellular bridge depletion modestly impacts the RNA landscape in early germ cell stages, while mutant cells that progress to late spermatocyte and post-meiotic spermatid stages broadly upregulate retrotransposons and dysregulate gene expression. RNA-sequencing confirms extensive sharing of transcripts between normal spermatids and demonstrates its partial attenuation in Tex14 hypomorphs, indicating that intercellular bridges enable exchange of cytoplasmic material between connected germ cells in testes. Tex14 hypomorphs display a progressive decline in germ cell numbers starting from the spermatocyte stage, with a complete lack of elongating spermatids, and are therefore sterile. Our findings reveal that the regulation of meiosis is non-cell-intrinsic and inform a model in which intercellular bridges orchestrate critical meiotic events and protect germline genome integrity during spermatogenesis, possibly by facilitating the exchange of regulatory factors.
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